The overall goal of this Program is to continue investigations into the molecular biology and biochemistry of signal transduction events leading to lymphocyte development, activation, and malignant transformation. Additionally, we will be studying how signaling modules, typically thought of as regulators of immune cell function, when expressed in other lineages, may lead to development of cancer. The projects of this Program are united by their interests in how multimolecular complexes regulate either appropriate or pathologic signaling outcomes. Thus each project of the Program will address, in some way, how particular intermolecular interactions regulate cellular function. Three of the projects of this Program are continuations from previous work and the fourth project is led by an investigator who joined the faculty at Penn during the course of our last period of funding and who has interacted extensively with each of our investigators. Project 1 extends work from the last period of funding examining the role of SH2 domain containing leukocyte phosphoprotein of 76 kDa (SLP-76) and its associated molecules as regulators of lymphocyte signaling. In this project the emphasis will be on how SLP-76 and its partner proteins function to coordinate integrin activation in T cells and neutrophils. Project 2 is new to this Program and investigates signaling complexes which form not at the site of T cell receptor antigen contact but instead at the distal pole of the cell. The third project in this program extends previous work studying immunoreceptors in B cells to the novel observation that such signaling in epithelial cells may lead to malignant transformation. The final project of the Program follows on previous work examining targets of Notch to investigate the role of TRIBBL homolog 2 as a key inducer of acute myelogeneous leukemia. The four projects bring together four established investigators, each with thriving individual research programs, who wish to continue their interactions through this joint effort. The program will be supported by an Administrative Core and two Scientific Cores. The first Scientific Core will assist in analysis of in vivo structure function relationships of critical signaling molecules using a retroviral transduction approach into bone marrow or fetal liver progenitor cells. The second Scientific Core, led by a fifth investigator associated with our program, will continue to provide expertise in image analysis, assisting each project in visualizing intermolecular complexes. Both of these cores added a great deal to the research efforts of each of our investigators during the first period of funding. We anticipate that our collective efforts will provide new insights into how signals are transduced leading to appropriate cellular responses and how these processes may go awry leading to pathologic consequences.